Bruton's tyrosine kinase (BTK) is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells and a key regulator of B-cell development, activation, signaling, and survival. It plays an essential role in the B-cell signaling pathway linking cell surface B-cell receptor (BCR) stimulation to downstream intracellular responses. Thus, among others, BTK contributes to the proliferation and survival of B cells, which are the white blood cells that turn malignant in mantle cell lymphoma.
Ibrutinib is the first BTK inhibitor approved by the U.S. Food and Drug Administration for the treatment of mantle cell lymphoma. Ibrutinib has a structure of formula (I), with a chemical name as 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one.

Polymorphism of ibrutinib has been reported in WO2013184572, which discloses six crystalline forms of ibrutinib, including 3 anhydrous forms and 3 solvates (i.e., methyl isobutyl ketone solvate, toluene solvate, and methanol solvate, respectively), obtained through screening a large number of solvent systems, including their mixtures. The two better-studied unsolvated forms of ibrutinib were reported to have low solubility (Form A 0.013 mg/mL at pH=8 and Form B 0.0096 mg/mL at pH=7.42). Moreover, the solvate forms are not suitable for use directly in dosage forms.
Therefore, new crystalline forms of ibrutinib, in particular stable unsolvated polymorphs with superior pharmacological properties remain a great need.